The present invention is in the field of medicine, particularly in the treatment of Type II diabetes and obesity. More specifically, the present invention relates to xcex23 adrenergic receptor agonists useful in the treatment of Type II diabetes and obesity.
The current preferred treatment for Type II, non-insulin dependent diabetes as well as obesity is diet and exercise, with a view toward weight reduction and improved insulin sensitivity. Patient compliance, however, is usually poor. The problem is compounded by the fact that there are currently no approved medications that adequately treat either Type II diabetes or obesity.
One therapeutic opportunity that has recently been recognized involves the relationship between adrenergic receptor stimulation and anti-hyperglycemic effects. Compounds that act as xcex23 receptor agonists have been shown to exhibit a marked effect on lipolysis, thermogenesis and serum glucose levels in animal models of Type II (non-insulin dependent) diabetes.
The xcex23 receptor, which is found in several types of human tissue including human fat tissue, has roughly 50% homology to the xcex21 and xcex22 receptor subtypes yet is considerably less abundant. Stimulation of the xcex21 and xcex22 receptors can cause adverse effects such as tachycardia, arrhythmia, or tremors. An agonist that is selective for the xcex23 receptor over the xcex21 and xcex22 receptors is, therefore, more desirable for treating Type II diabetes or obesity relative to a non-selective agonist.
However, recent studies have suggested the presence of an atypical beta receptor associated with atrial tachycardia in rats (Br. J. of Pharmacol., 118:2085-2098, 1996). In other words, compounds that are not agonists of the xcex21 and xcex22 receptors can still modulate tachycardia through activation of a yet to be discovered xcex24 or through some other unknown pathway.
A large number of publications have appeared in recent years reporting success in discovery of agents that stimulate the xcex23 receptor. Despite these recent developments, there remains a need to develop a selective xcex23 receptor agonist which has minimal agonist activity against the xcex21 and xcex22 receptors.
The present invention relates to a compound of formula I: 
wherein:
A1, A2 and A3 are carbon or nitrogen provided that only one of A1, A2 and A3 can be nitrogen;
Het is an optionally substituted, optionally benzofused 5 or 6 membered heterocyclic ring;
R1, R1a and R1b are independently H, halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 haloalkyl, or SO2(C1-C6 alkyl);
R2 is H or C1-C6 alkyl;
R3 is H or C1-C6 alkyl;
R4 is H or C1-C6 alkyl;
or R3 and R4 combine with the carbon to which both are attached to form a C3-C6 cyclic ring;
or R4 and X1 combine with the carbon to which both are attached to form a C3-C8 cyclic ring;
or R4 combines with X1, the carbon to which both are attached, and the phenyl group to which X1 is attached to form: 
xe2x80x83wherein:
n and m are independently 0, 1, 2, or 3 provided that the sum of n+m is xe2x89xa64 and that R3 is H;
X is OCH2, SCH2 or a bond;
X1 is a bond or a C1-C5 divalent hydrocarbon moiety;
X2 is O, S, NH, NHSO2, SO2NH, CH2 or a bond; and
X3 is optionally substituted phenyl or an optionally substituted 5 or 6 membered heterocyclic ring; or a pharmaceutical salt thereof.
The present invention also relates to processes for preparing, as well as novel pharmaceutical formulations containing, a compound of formula I. In another embodiment, the pharmaceutical formulations of the present invention may be adapted for use in treating Type II diabetes and obesity and for agonizing the xcex23 receptor.
The present invention also relates to methods for treating Type II diabetes and obesity, as well as a method for agonizing the xcex23 receptor employing a compound of formula I.
In addition, the present invention relates to a compound of formula I for use in treating Type II diabetes and obesity as well as a compound of formula I for use in agonizing the xcex23 receptor. The present invention is further related to the use of a compound of formula I for the manufacture of a medicament for treating Type II diabetes and obesity as a well as for agonizing the xcex23 receptor.
The present invention is also related to a compound of formula II: 
which is useful as an intermediate to prepare a compound of formula I.
For the purposes of the present invention, as disclosed and claimed herein, the following terms are defined below.
The term xe2x80x9chaloxe2x80x9d represents fluoro, chloro, bromo, or iodo.
The terms xe2x80x9cC1-C6 alkylxe2x80x9d and xe2x80x9cC1-C4 alkylxe2x80x9d represent a straight, branched or cyclic hydrocarbon moiety having from one to six and one to four carbon atoms, respectively. C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and cyclobutyl. A xe2x80x9cC1-C4 haloalkylxe2x80x9d group is a C1-C4 alkyl moiety substituted with up to six halo atoms, preferably one to three halo atoms. An example of a haloalkyl group is trifluoromethyl. A xe2x80x9cC1-C6 alkoxyxe2x80x9d group is a C1-C6 alkyl moiety connected through an oxy linkage.
The term xe2x80x9cdivalent hydrocarbon moietyxe2x80x9d refers to a straight or branched chain of carbon atoms that may optionally have one or more points of unsaturation. Thus, a hydrocarbon diradical according to the present invention includes alkylene, alkenylene and alkylidene moieties. Examples include but are not intended to be limited to methylene, ethylene, propylene, butylene, xe2x80x94CH(CH3)CH2xe2x80x94xe2x80x94CH(C2H5)CH2xe2x80x94, xe2x80x94CH(CH3)CH(CH3)xe2x80x94, xe2x80x94CH2C(CH3)2xe2x80x94, xe2x80x94CH2CH(CH3)CH2xe2x80x94, xe2x80x94C(CH3)2CH2xe2x80x94, xe2x80x94CHxe2x95x90CHCH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x95x90CCH2xe2x80x94, and the like.
The term xe2x80x9coptionally substitutedxe2x80x9d as used herein means an optional substitution of one to three, preferably one or two groups independently selected from oxo, nitro, cyano, phenyl, benzyl, halo, C1-C6 alkyl, C1-C4 haloalkyl, COR5, NR6R6, NR6COR5, NR6SO2R7, OR6, OCOR5, OSO2R7, SR6, SOR7, SO2R7 or SO2NR6R6; wherein
R5 is H, C1-C6 alkyl, phenyl, benzyl, C1-C4 haloalkyl, NR6aR6a or OR6a;
R6 and R6a are independently H, C1-C6 alkyl or phenyl; or when two R6 or R6a groups are attached to the same nitrogen atom, said R6 or R6a groups, together with the nitrogen to which they are attached, may combine to form a piperidine, pyrrolidine, hexamethyleneimine or morpholine ring; and
R7 is C1-C6 alkyl or phenyl.
The term xe2x80x9cheterocyclic ringxe2x80x9d represents a stable, saturated, partially unsaturated, fully unsaturated or aromatic ring, said ring having from one to four heteroatoms that are independently selected from the group consisting of sulfur, oxygen, and nitrogen. The heterocycle may be attached at any point which affords a stable structure. Representative heterocyclic rings include 1,3-dioxolane, 4,5-dihydro-1H-imidazole, 4,5-dihydrooxazole, furan, imidazole, imidazolidine, isothiazole, isoxazole, morpholine, oxadiazole, oxazole, oxazolidinedione, oxazolidone, piperazine, piperidine, pyrazine, pyrazole, pyrazoline, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrazole, thiadiazole, thiazole, thiophene and triazole. Representative xe2x80x9cbenzofusedxe2x80x9d heterocyclic rings include benzoxazole, benzimidazole, benzofuran, benzothiophene, benzothiazole, azaindole, and indole. Further specific examples of benzofused and non-benzofused heterocycles are described below in the Preparations and Examples sections.
The term xe2x80x9csuitable solventxe2x80x9d refers to any solvent, or mixture of solvents, inert to the ongoing reaction that sufficiently solubilizes the reactants to afford a medium within which to effect the desired reaction.
The term xe2x80x9cpatientxe2x80x9d includes human and non-human animals such as companion animals (dogs and cats and the like) and livestock animals. Livestock animals are animals raised for food production. Ruminants or xe2x80x9ccud-chewingxe2x80x9d animals such as cows, bulls, heifers, steers, sheep, buffalo, bison, goats and antelopes are examples of livestock. Other examples of livestock include pigs and avians (poultry) such as chickens, ducks, turkeys and geese. Yet other examples of livestock include fish, shellfish and crustaceans raised in aquaculture. Also included are exotic animals used in food production such as alligators, water buffalo and ratites (e.g., emu, rheas or ostriches). The preferred patient of treatment is a human.
The terms xe2x80x9ctreatingxe2x80x9d and xe2x80x9ctreatxe2x80x9d, as used herein, include their generally accepted meanings, i.e., preventing, prohibiting, restraining, alleviating, ameliorating, slowing, stopping, or reversing the progression or severity of a pathological condition, or sequela thereof, described herein.
The terms xe2x80x9cpreventingxe2x80x9d, xe2x80x9cprevention ofxe2x80x9d, xe2x80x9cprophylaxisxe2x80x9d, xe2x80x9cprophylacticxe2x80x9d and xe2x80x9cpreventxe2x80x9d are used herein interchangeably and refer to reducing the likelihood that the recipient of a compound of formula I will incur or develop any of the pathological conditions, or sequela thereof, described herein.
As used herein, the term xe2x80x9ceffective amountxe2x80x9d means an amount of a compound of formula I that is capable of treating conditions, or detrimental effects thereof, described herein or that is capable of agonizing the xcex23 receptor.
The term xe2x80x9cselective xcex23 receptor agonistxe2x80x9d means a compound that displays preferential agonism of the xcex23 receptor over agonism of the xcex21 or xcex22 receptor. Thus, xcex23 selective compounds behave as agonists for the xcex23 receptor at lower concentrations than that required for similar agonism at the xcex21 and xcex22 receptors. A xcex23 selective compound also includes compounds that behave as agonists for the xcex23 receptor and as antagonists for the xcex21 and xcex22 receptors.
The term xe2x80x9cpharmaceuticalxe2x80x9d when used herein as an adjective means substantially non-deleterious to the recipient patient.
The term xe2x80x9cformulationxe2x80x9d, as in pharmaceutical formulation, is intended to encompass a product comprising the active ingredient(s) (compound of formula I), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical formulations of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutical carrier.
The term xe2x80x9cunit dosage formxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other non-human animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
Because certain compounds of the invention contain an acidic moiety (e.g., carboxy), the compound of formula I may exist as a pharmaceutical base addition salt thereof. Such salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like.
Because certain compounds of the invention contain a basic moiety (e.g., amino), the compound of formula I can also exist as a pharmaceutical acid addition salt. Such salts include the salicylate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, mono-hydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butyne-1,4 dioate, 3-hexyne-2,5-dioate, benzoate, chlorobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, xcex2-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and like salts. Preferred acid addition salts include the hemi-fumarate, benzoate, salicylate, R-mandelate, hydrochloride and glycolate salts.
It is recognized that various stereoisomeric forms of a compound of formula I exist. The compounds may be prepared as racemates and can be conveniently used as such. Therefore, the racemates, individual enantiomers, diastereomers, or mixtures thereof form part of the present invention. Unless otherwise specified, whenever a compound is described or referenced in this specification all the racemates, individual enantiomers, diastereomers, or mixtures thereof are included in said reference or description.
It is also recognized that various tautomeric forms of a compound of formula I may exist, and all tautomeric forms are part of the present invention. Unless otherwise specified, whenever a compound is described or referenced in this specification all tautomeric forms, or mixtures thereof, are included in said reference or description.
Certain compounds of the invention are particularly interesting and are preferred. The following listing sets out several groups of preferred compounds. It will be understood that each of the listings may be combined with other listings to create additional groups of preferred compounds.
a) A1, A2 and A3 are carbon;
b) Het is at the ortho-position relative to X;
c) Het is optionally substituted one to three times independently with halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, COR8, CO2R8, CONR8R8, NR8R8, NHCO(C1-C4 alkyl), NHCO(phenyl), NHCO(benzyl), SR8, SO(C1-C4 alkyl), SO2(C1-C4 alkyl), SO2(NR8R8), OCO(C1-C4 alkyl), OCO2R8 or OCONR8R8 where R8 is independently at each occurrence H or C1-C4 alkyl;
d) Het is an optionally substituted 5-membered, non-benzofused ring containing one or two heteroatoms that are independently selected from the group consisting of sulfur, oxygen, and nitrogen;
e) Het is selected from furan; isothiazole; isoxazole; oxazole; and thiophene; wherein said Het moieties are optionally substituted once with fluorine, methyl, cyano, SO2NH2 or COCH3;
f) Het is selected from thien-2-yl; thien-3-yl; thiazol-2-yl; isoxazol-3-yl; isoxazol-5-yl; and isothiazol-5-yl;
g) Het is thien-2-yl optionally substituted once with fluorine, methyl, cyano, SO2NH2 or COCH3;
h) Het is thien-2-yl;
i) R1, R1a and R1b are independently H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, or SO2(C1-C4 alkyl);
j) R1 is H, methyl, ethyl, CF3, chloro or fluoro;
k) R1 is H, methyl, chloro or fluoro;
l) R1 is H or fluoro;
m) R1 is H;
n) R1a is H, methyl, ethyl, CF3, chloro or fluoro;
o) R1a is H, methyl, chloro or fluoro;
p) R1a is H;
q) R1b is H, methyl, ethyl, CF3, chloro or fluoro;
r) R1b is H, methyl, chloro or fluoro;
s) R1b is H;
t) R2 is H or C1-C4 alkyl;
u) R2 is H;
v) R3 and R4 are independently H or C1-C4 alkyl;
w) R3 is H or methyl;
x) R4 is H or methyl;
y) R3 and R4 are both methyl;
z) R8 is independently at each occurrence H or C1-C4 alkyl;
aa) X is OCH2;
bb) X1 is a bond, methylene or ethylene;
cc) X1 is methylene;
dd) X2 is at the para-position relative to X1;
ee) X2 is a bond or O;
ff) X2 is O or CH2;
gg) X2 is O;
hh) X3 is optionally substituted one to three times independently with halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, COR8, CO2R8, CONR8R8, NR8R8, NHCO(C1-C4 alkyl), NHCO(phenyl), NHCO(benzyl), SR8, SO(C1-C4 alkyl), SO2(C1-C4 alkyl), SO2(NR8R8), OCO(C1-C4 alkyl), OCO2R8 or OCONR8R8;
ii) X3 is phenyl, pyridyl, thienyl or furanyl wherein said X3 moieties are substituted one to three times with fluoro, chloro, cyano, hydroxy, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, amino, CO2CH3, CO2CH2CH3, CONR8R8, SCH3, SCH2CH3, SOCH3, SOCH2CH3, SO2CH3 or SO2CH2CH3;
jj) X3 is phenyl, pyridyl, thienyl or furanyl wherein said X3 moieties are substituted one to three times with fluoro, cyano, hydroxy, methyl, ethyl, methoxy, ethoxy, amino, CO2CH3, CO2CH2CH3, CONH2, SCH3, SCH2CH3, SOCH3, SOCH2CH3, SO2CH3 or SO2CH2CH3;
kk) X3 is phenyl, pyridyl, thienyl or furanyl wherein said X3 moieties are substituted one to three times with fluoro, amino, CO2CH3, CO2CH2CH3, cyano, CONH2, SO2CH3 or SO2CH2CH3;
ll) X3 is phenyl, pyridyl or pyridazinyl wherein said X3 moieties are substituted once or twice with chloro, cyano, CONH2 or SO2CH3;
mm) X3 is phenyl, pyridyl, thienyl or furanyl wherein said X3 moieties are substituted once with cyano or CONH2;
nn) X3 is phenyl or pyridyl wherein said X3 moieties are substituted once with cyano or CONH2;
oo) X3 is pyridyl substituted once with cyano or CONH2;
pp) X3 is 5-cyano or 5-carboxamido-pyrid-2-yl;
qq) X3 is 4-cyano or 4-carboxamido-phenyl;
rr) X3 is 3-cyano or 3-carboxamido-pyrid-2-yl;
ss) X3 is 2-cyano or 2-carboxamido-phenyl;
tt) the compound of formula I is an acid addition salt;
uu) the compound of formula I is the hydrochloride salt;
vv) the compound of formula I is the glycolate salt;
ww) the compound of formula I is the hemi-fumarate salt.
Synthesis
The compound of formula I may be prepared as described in the following Schemes and Examples. 
The reaction of Scheme 1 may be carried out under conditions appreciated in the art for the amination of epoxides. For example, the epoxide of formula II may be combined with an amine of formula III in a lower alcohol, dimethylformamide, dimethylsulfoxide, or acetone, preferably ethanol, isopropanol, n-butanol or t-butanal, at room temperature to the reflux temperature of the reaction mixture, preferably between 40xc2x0 C.-90xc2x0 C. The reaction may also be carried out under conditions generally described in Atkins, et al., Tet. Let., 27:2451, 1986. These conditions include mixing the reagents in the presence of trimethylsilyl acetamide in a polar aprotic solvent such as acetonitrile, dimethylformamide, acetone, dimethylsulfoxide, dioxane, diethylene glycol dimethyl ether, tetrahydrofuran, or other polar aprotic solvents in which the reagents are soluble.
The compound of formula I may also be prepared via a Suzuki coupling as shown in Scheme 2. 
A compound of formula IV may be reacted with a compound of formula III as described above in Scheme 1. The compound of formula V (an aryl halide) may then be reacted with a heteroaryl boronic acid, an aryl boronic ester, or an aryl boronic cyclic ester, preferably an aryl boronic acid, under conditions appreciated in the art for the coupling of aromatic halides with aryl boronic acids and their derivatives. This coupling is known in the art generally as a Suzuki coupling. The skilled artisan will recognize that an aryl triflate may also be employed in the present Suzuki coupling as an alternative to employing an aryl halide.
The epoxide starting materials employed in Schemes 1 and 2 may be prepared by techniques recognized and appreciated by one skilled in the art. See, e.g., U.S. Pat. No. 4,663,334; European Patent Application 171209; Korn, et al., J. Pharm. Sci., 69(9):1010-13, 1980 and references cited below in the Preparations section for representative and/or analogous procedures for preparing the epoxides of formula II and IV. To illustrate, epoxides of formula II, where X is OCH2 or SCH2, may be prepared according to the procedure detailed in Scheme 3 wherein R9 is OH or SH and Xxe2x80x2 is OCH2 or SCH2. 
Equimolar amounts of a compound of formula VI and (2S)-(+)-glycidyl 3-nitrobenzenesulfonate may be dissolved in an inert solvent such as acetone and treated with a slight excess of a weak base, such as potassium carbonate. The suspension may then be heated at reflux for 16-20 hours with stirring to provide a compound of formula II(a). Compounds of formula IV, where X is OCH2 or SCH2, may be prepared in an analogous fashion.
The amino starting materials employed in Schemes 1 and 2 (formula III compound) may also be prepared by techniques recognized and appreciated by one skilled in the art. For example, an amine of formula III, where X2 is O, may be prepared according to the procedure detailed in Scheme 4. 
A compound of formula IX may be prepared by reacting an arylalkyl alcohol of formula VII with excess (5 mol/equivalent) formula VIII compound by methods well known in the art (see, e.g., Sh. Prikl. Kin., 45:1573-77, 1972). The reaction may also be carried out by mixing the reagents in an aprotic solvent, preferably diglyme, and adding potassium t-butoxide (0.5 mol/equivalent). The reaction is typically heated at reflux until water present in the reaction mixture is removed (generally 2-8 hours). A compound of formula X may then be prepared by hydrogenation of the corresponding compound of formula IX over a precious metal catalyst. The hydrogenation can be affected at between 20 and 60 psi of hydrogen (preferably 50 psi), and with a variety of solvents (preferably methanol/acetic acid), temperatures (preferably 50xc2x0 C.), and catalysts (preferably 5% palladium on carbon wetted with ethanol denatured with toluene) well known in the art.
A skilled artisan will appreciate that a compound of formula X could be coupled with a wide variety of halides to yield the claimed ethers. The coupling can be carried out according to procedures well known in the art and is preferably performed by mixing the starting materials in N,N-dimethylacetamide and toluene in the presence of potassium carbonate. The reaction is typically then heated to reflux for 5 to 24 hours to effect the reaction and to remove water present in the reaction mixture.
Compounds of formula VI, VII and VIII are either commercially available, known in the art, or can be prepared by methods known in the art or described herein.
The following Preparations, Examples and Formulations are provided so that the invention might be more fully understood. They should not be construed as limiting the invention in any way.
Epoxides of Formula II and IV
Epoxides 1-21, 23-54 and 56-74 are prepared for use as described in Scheme 1. Epoxides 22 and 55 are prepared for use as described in Scheme 2. These epoxides are pictured in Tables 1 and 2 below.
A mixture of 2-(1-methylpyrazol-5-yl)phenol (4.65 mmol, 810 mg), (2S)-glycidyl 3-nitrobenzenesulfonate (5.58 mmol, 1.45 g), potassium carbonate (5.58 mmol, 771 mg) and acetone (40 ml) are refluxed for 16 hours, cooled to room temperature and the solids removed via filtration. The filtrate is concentrated and the crude product purified on silica gel (40% ethyl acetate/hexane) to give 956 mg of the title epoxide.
Methyl hydrazine (23.2 mmol, 1.23 ml) is added to a solution of 2-(3-hydroxy-2-propen-1-on-1yl)phenol (J. Am. Chem. Soc., 72:3396, 1950), 15.4 mmol, 2.54 g) in methanol (7 ml) and the mixture is heated at 100xc2x0 C. for one hour. After cooling, the reaction mixture is diluted with water (100 ml) and stirred for one hour. The precipitate is collected via filtration and purified on silica gel (30% ethyl acetate/hexane) to give 811 mg of 2-(1-methylpyrazol-3-yl)phenol.
A mixture of 2-(1-methylpyrazol-3-yl)phenol (4.59 mmol, 800 mg), (2S)-glycidyl 3-nitrobenzenesulfonate (5.51 mmol, 1.42 g), potassium t-butoxide (5.51 mmol, 515 mg) and tetrahydrofuran (30 ml) are refluxed for 16 hours, cooled to room temperature and poured into saturated aqueous ammonium chloride. The aqueous layer is extracted with ethyl acetate (3xc3x97) and the extracts washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The crude product is purified on silica gel (40% ethyl acetate/hexane) to give 785 mg of the title epoxide.
A mixture of 2-(pyrazol-5-yl)phenol (Catalan, et al., J. Am. Chem. Soc., 114(13):5039-48, 1992, 10 mmol, 1.60 g), triethylamine (40.0 mmol, 5.6 ml), and acetonitrile (55 ml) is cooled in an ice bath under N2 and treated dropwise with chlorotrimethylsilane (12.0 mmol, 1.52 ml). After the addition is complete, the cold bath is removed and the reaction mixture stirred at ambient temperature for 1 hour. The reaction mixture is then treated with trityl chloride (10.0 mmol, 2.78 g) and stirred at ambient temperature overnight, followed by refluxing for 1 hour. The reaction mixture is concentrated, treated with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate (3xc3x9750 ml). The extracts are dried over magnesium sulfate and concentrated to a viscous oil. The oil is crystallized from 20% ethyl acetate/hexane to give 1.72 g of N-trityl-2-(pyrazol-5-yl)phenol.
A solution of this intermediate phenol (4.27 mmol, 1.72 g) is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate (4.27 mmol, 1.11 g) substantially as decribed for epoxide 2 except that the present reaction is refluxed for 48 hours and the crude product is purified via crystallization from ethyl acetate to give 860 mg of the title epoxide.
Phenylhydrazine (476 mmol, 51.5 g) and 2-hydroxyacetophenone (476 mmol, 64.8 g) are stirred under reflux in dry ethanol (280 ml) for 6 hours. After cooling, the crystals are filtered off, washed with cold ethanol and dried under vacuum at 50xc2x0 C. to yield 73 g (68%) of the hydrazone, which is then mixed with nickel chloride (7 g) and heated under a nitrogen atmosphere to 240xc2x0 C. for 3 hours. After cooling, the mixture is suspended in dichloromethane (800 ml), salt is removed by filtration and the filtrate is concentrated. The resulting crystals are filtered off, washed with dichloromethane (50 ml) and dried in vacuo at 40xc2x0 C. to give 16.1 g of 2-(2-indolyl)phenol (24%). This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
2-Hydroxyacetophenone (220 mmol, 30 g) is stirred in a mixture of dimethylformamide-dimethyl acetal for 5 hours at 70xc2x0 C., cooled and recrystallised from diethylether. The intermediate is dissolved in dry ethanol (200 ml) and formamidine acetate (0.61 mmol, 63.5 g) is added. A solution of sodium (0.61 mol, 14 g) in ethanol (450 ml) is added in several portions and the mixture is refluxed for 18 hours and evaporated. Recrystallisation from diisopropylether yielded 3.6 g (10%) of 2-(pyrimidin-4-yl)phenol as a solid. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
A mixture of 4-chloro-2-hydroxybenzoic acid hydrazide (Chemical Abstracts, 93:7808, 475 mg, 2.55 mmol) and triethylorthoformate. (3.6 ml) is heated at 130xc2x0 C. for 3.5 hours. After cooling, a precipitate formed and is collected by filtration. The filter cake is recrystallized from methanol to give 173 mg (35%) of 5-chloro-2-(1,3,4-oxadiazol-2-yl)phenol. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield 170 mg (69%) of the title epoxide.
A mixture of methyl 3-hydroxybenzoate (5.48 g, 36.0 mmol) and 1,2-diaminoethane monotosylate (9.85 g, 42.4 mmol) is heated at 210xc2x0 C. for 7 hours. After cooling, the mixture is stirred with aqueous 2N sodium hydroxide and extracted with ethyl acetate. The precipitate which formed and is present in the aqueous layer is collected by filtration and dried in vacuo to give 1.3 g (22%) of 2-(3-hydroxyphenyl)imidazoline.
To a solution of 2-(3-hydroxyphenyl)imidazoline (0.895 g, 5.52 mmol) in tetrahydrofuran (11 ml) is added water (11 ml), potassium carbonate (1.5 g, 10.8 mmol), then di-t-butyl-dicarbonate (1.2 g, 5.5 mmol). The resulting mixture is stirred over night before additional di-t-butyl-dicarbonate (120 mg) is added and the stirring is continued for several hours. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified via chromatography on silica gel with dichloromethane/ethanol (gradient up to 20:1) to give 615 mg of t-butyl (2-(3-hydroxyphenyl)imidazolin-1-yl)carboxylate (42%). This Boc-protected product (610 mg, 2.33 mmol) is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield 720 mg (97%) of the title epoxide.
A mixture of 2-iodophenol (5.00 g, 22.7 mmol), (2S)-glycidyl 3-nitrobenzenesulfonate (5.89 g, 22.7 mmol) and potassium carbonate (3.44 g, 24.9 mmol) in methylethylketone (150 ml) is refluxed for 18 hours. After cooling, the salts are removed by filtration. The filter cake is rinsed thoroughly with dichloromethane and the collected filtrates are evaporated. The residue is purified via flash chromatography on silica gel using a hexane-hexane/ethyl acetate gradient (100 to 90:10).
Sodium (1.21 g, 52.6 mmol) is added to 200 ml methanol to prepare a solution of sodium methoxide. After addition of guanidine hydrochloride (12.41 g, 129.9 mmol) and 3-(dimethylamino)-1-(2-hydroxyphenyl)-2-propen-1-one (5.0 g, 26.15 mmol; J. Heterocyclic Chem., 14:345, 1977) the mixture is heated at reflux over night. The reaction solvent is removed under reduced pressure, and the residue treated with water. The resulting precipitate is collected by filtration and dried in vacuo to give 4.25 g of 2-amino-4-(2-hydroxyphenyl)pyrimidine (87%). This pyrimidine pre-cursor is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 2.05 g of the title epoxide (37.5%).
A mixture of 3-hydroxyacetophenone (20.0 g, 146.9 mmol) and N,N-dimethylformamide dimethyl acetal (26.26 g, 220.4 mmol) is heated over night at 100xc2x0 C. The excess of the acetal is removed under reduced pressure and 3-(dimethylamino)-1-(3-hydroxyphenyl)-2-propen-1-one (10.32 g, 37%) is obtained after chromatography on silica gel with dichloromethane/ethanol 9:1. This intermediate enone is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 5.02 g of the title epoxide (78%).
A solution of 3-(dimethylamino)-1-(3-hydroxyphenyl)-2-propen-1-one (2.2 g, 11.5 mmol) and hydroxylamine hydrochloride (1.17 g, 16.8 mmol) in 45 ml dioxane/water 1:1 is heated for 2 hours at 60xc2x0 C. The reaction is poured into ice-water and the precipitate is collected by filtration, washed with water, and dried in vacuo to give 1.4 g of 3-(5-isoxazolyl)phenol (75.5%). This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 1.33 g of the title epoxide (70%).
2-Amino-4-(3-hydroxyphenyl)pyrimidine, prepared substantially as described for 2-amino-4-(2-hydroxyphenyl)pyrimidine, is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give the title epoxide.
To dioxane (113 ml) is added 2-methoxy-5-fluorophenylboronic acid (4.25 g, 24.9 mmol), 2-bromothiophene (3.65 g, 22.7 mmol, 0.9 eq.) and potassium carbonate (2M, 37 ml). Palladium (0) tetrakistriphenylphoshine (0.03 eq.) is then added and the resulting mixture is heated to 85xc2x0 C. for 3 hours. The reaction is cooled to room temperature and poured into ethyl acetate and water. The aqueous layer is extracted twice with ethyl acetate. The organic layers are combined, and dried over sodium sulfate, concentrated to a brown oil and the resulting residue is flash chromatographed in 20% toluene/hexanes to afford 11.5 g of 2-(thien-2-yl)-4-fluoroanisole (90%).
The protected product from above (11.0 g, 52.8 mmol) is demethylated with 110 grams of pyridine hydrochloride neat at 200 degrees for 3 hours. The reaction is poured into ice/water and ethyl acetate is added. The layers are separated and the organic layer is washed with water, dried over sodium sulfate and concentrated to a brown solid. This is then flash chromatographed with 1:3 ethyl acetate/hexanes to afford 7.82 g of 2-(thien-2-yl)-4-fluorophenol (77% yield). This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
Epoxide 31 is prepared from 2-methoxy-6-flourophenylboronic acid and 2-bromothiophene by a procedure substantially similar to that described for Epoxide 30.
A mixture of 2-methoxybenzaldehyde (10.0 g, 73.4 mmol), tosylmethylisocyanide (14.34 g, 73.4 mmol) and potassium carbonate (10.14 g, 73.4 mmol) in 220 ml methanol is heated at reflux for 6 hours. The solvent is removed under reduced pressure and the residue poured into ice-water (800 ml). The precipitate is collected by filtration, washed with water, and dried in vacuo to give 9.05 g of 5-(2-methoxyphenyl)oxazole (70%).
Boron tribromide (1M in dichloromethane, 36 ml) is added slowly to a cold solution (0xc2x0 C.) of the above oxazole (3.0 g, 17.1 mmol) in dichloromethane (215 ml). After stirring over night at room temperature, ice-water (50 ml) is added carefully. The aqueous layer is extracted with dichloromethane (50 ml), and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The precipitate which formed after addition of dichloromethane (70 ml) is collected by filtration, heated with dichloromethane (15 ml), and filtered again to give 3.16 g of 2-(5-oxazolyl)phenol. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 400 mg of the title epoxide (9.5%).
2-Methoxyphenylboronic acid (2 eq.) and pyrazole (1 eq.) are coupled with copper(II) acetate catalysis as described in Tetrahedron Lett. 39:2941-44, 1998 and the product is demethylated by treatment with boron tribromide in dichloromethane (see, for example, Synth. Commun. 27(20):3581-90, 1997) to yield 2-(pyrazol-1-yl)phenol. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give the title epoxide.
2-(Imidazolidin-2-on-1-yl)anisole (Ger. Offen. 1977, DE 2528079) is demethylated with boron tribromide and the resulting 2-(imidazolidin-2-on-1-yl)phenol is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
2-(Imidazol-1-yl)anisole (L. M. Sitkina, A. M. Simonov, Khim. Geterotsikl. Soedin 1966, 143) is demethylated with boron tribromide and the resulting 2-(imidazol-1-yl)phenol is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give the title epoxide.
3-(Dimethylamino)-1-(4-hydroxyphenyl)-2-propen-1-one is prepared from 4-hydroxyacetophenone substantially in the same manner as that described for 3-(dimethylamino)-1-(3-hydroxyphenyl)-2-propen-1-one (Epoxide 24). 4-(5-Isoxazolyl)phenol is prepared from 3-(dimethylamino)-1-(4-hydroxyphenyl)-2-propen-1-one substantially in the same manner as that described for 3-(5-isoxazolyl)phenol (Epoxide 25). This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
2-(3-Formyl-1-pyrrolyl)phenol (3 g, 16 mmol) and triethylamine (17.6 mmol) are added to a suspension of hydroxylamine hydrochloride (1.22 g, 17.6 mmol) in acetic anhydride (7.7 ml) and the mixture is allowed to stir overnight at ambient temperature. The mixture is refluxed for 5 hours, concentrated, dissolved in 50 ml ethanol and stirred for 10 min with 50 ml 2 M aqueous sodium hydroxide. After neutralisation with aqueous hydrochloric acid, and extraction with ethylacetate, the organic layer is dried and concentrated. The residue is purified by chromatography (toluene/ethanol 9:1) to yield 2-(3-cyano-1-pyrrolyl)phenol (2.4 g, 92%). This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
To 2-(3-formyl-1-pyrrolyl)phenol (2.9 g, 15.5 mmol) in 50 ml dry tetrahydrofuran are added sodium cyanoborohydride (1.94 g, 31 mmol) and boron trifluoride diethyletherate (5.7 ml, 47 mmol). The resulting solution is stirred for 3 hours at ambient temperature. Saturated sodium bicarbonate (100 ml) is added and the resulting mixture is stirred for 1 hour before extraction with t-butylmethylether. The organic layer is dried and concentrated and the residue is purified by chromatography (toluene/ethanol 9:1) to yield 2-(3-methyl-1-pyrrolyl)phenol (300 mg, 11%). This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
2-Bromo-5-fluoro-phenol (0.87 ml, 7.9 mmol) and 2-thiopheneboronic acid (2.02 g, 15.8 mmol) are dissolved in 100 ml dioxane. The resultingsolution is flushed with argon before tetrakis(triphenylphosphine)palladium (456 mg, 0.395 mmol) and 2 ml of aqueous 2M sodium carbonate solution (20 mmol) are added. After flushing again with argon the mixture is refluxed for 15 hours at 100xc2x0 C. The solution is allowed to cool to room temperature and the mixture is filtered. The filtrate is evaporated and the residue is taken up in dichloromethane and extracted with water. The organic layer is dried with sodium sulfate then concentrated. The residue is purified by chromatography (CH2Cl2/EtOH gradient 100:0 to 98:2) to yield 1.13 g of 2-(thien-2-yl)-5-fluorophenol (74%).
2-(Thien-2-yl)-5-fluorophenol and (2S)-glycidyl 3-nitrobenzenesulfonate are reacted as described for the preparation of Epoxide 1 to give the title epoxide.
2-Bromo-5-fluorophenol is coupled with thiophene-3-boronic acid; 2-bromo-4,5-difluorophenol is coupled with thiophene-2-boronic acid; and 2-bromo-4,5-difluorophenol is coupled with thiophene-3-boronic acid in Suzuki reactions substantially as described for Epoxide 48, to yield 2-(thien-3-yl)-5-fluorophenol; 2-(thien-2-yl)-4,5-difluorophenol; and 2-(thien-3-yl)-4,5-difluorophenol, respectively. These phenolic products are reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxides.
To a solution of 6-fluorochroman-4-one (21.0 g, 126 mmol) in acetic acid (105 ml) is added bromine (6.5 ml, 126 mmol) at such a rate as to not raise the temperature above 25xc2x0 C. After the addition is complete, the reaction is allowed to stir for 2 hours before pouring into 1 liter of ice. The resulting mixture is stirred over night. The precipitate which formed is filtered and placed in drying oven to produce 21 g of 3-bromo-6-fluorochroman-4-one.
The product from (14 g, 57 mmol) above is dissolved in triethylamine (100 ml) and is stirred at reflux for 2 hours. The reaction is cooled and concentrated, taken up in chloroform, washed with 2N aqueous hydrochloric acid and water. The organic layer is dried over sodium sulfate and concentrated. The product residue is crytallized from hot ethyl acetate.
The product from above (6-fluorochromen-4-one (5.25 g, 32.0 mmol) and hydroxylamine hydrochloride (4.65 g, 67.2 mmol) are dissolved in ethanol (180 ml) and the resulting mixture is heated to reflux. The reaction is allowed to stir for 18 hours before cooling and concentrating. The residue is is taken up in toluene and filtered to give 690 mg of 4-fluoro-2-(isoxazol-5-yl)phenol and from the filtrate 594 mg of 4-fluoro-2-(isoxazol-3-yl)phenol. These phenolic products are separately reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxides.
2-Fluoro-6-(thien-3-yl)anisole is prepared from 2-fluoro-6-iodoanisole (1.35 g, 5.36 mmol) by Suzuki coupling with thiophene-3-boronic acid according to the general procedure described in Representative Procedure 4(b) below; yield: 1.05 g (94%).
2-Fluoro-6-(thien-3-yl)phenol is obtained from the anisole (1.0 g, 4.8 mmol) with an excess of boron tribromide in dichloromethane by stirring over night. The crude phenol (1.1 g) is used for the next step without further purification.
Sodium hydride (0.18 g, 4.5 mmol, 60% in oil) is washed several times with hexane under argon and added to a solution of 2-fluoro-6-(thien-3-yl)phenol (0.44 g, 2.26 mmol) and (2S)-glycidyl 3-nitrobenzenesulfonate (0.587 g, 2.26 mmol) in dry tetrahydrofuran (20 ml). After stirring at room temperature over night, the mixture is quenched with ice-cold water, diluted with brine, and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, concentrated under reduced pressure, to give 65 mg (11%) of the title epoxide after chromatography (silica gel, dichloromethane).
A mixture of 2-bromo-1-(2-benzyloxyphenyl)ethanone (10.0 g, 32.77 mmol; prepared according to a procedure from J. Med. Chem., 35:3045, 1992) and sodium formate (4.46 g, 65.6 mmol) in dry DMF (100 ml) is stirred at room temperature over night. The mixture is poured into water (400 ml) and extracted with dichloromethane (2xc3x97100 ml). The combined extracts are dried over sodium sulfate and concentrated under reduced pressure.
The residue is dissolved in acetic acid (100 ml), treated with ammonium acetate (12.62 g, 163.7 mmol), and the mixture is heated for 3 hours. After cooling, the mixture is diluted with water (400 ml) and extracted with dichloromethane (2xc3x97100 ml). The combined organic layers are washed with saturated aqueous sodium bicarbonate solution (2xc3x97100 ml), dried over sodium sulfate, and concentrated in vacuo. 4-(2-Benzyloxyphenyl)oxazole (1.99 g, 24%) is obtained after chromatography (silica gel, dichloromethane).
To a solution of the oxazole from above (1.99 g, 7.92 mmol) in dichloromethane (20 ml) is added 10% palladium on carbon (1.99 g). The mixture is put under an atmosphere of hydrogen, stirred at room temperature over night, then filtered through Celite. The solvent is removed under reduced pressure to leave 2-(oxazol-4-yl)phenol (1.15 g, 90%), which is used for the next step without further purification.
The title epoxide (1.05 g, 72%) is prepared from the above phenol (1.08 g, 6.7 mmol) and (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1.
To a solution of 2-fluoro-6-iodoanisole (Justus Liebigs, Ann. Chem., 746:134, 1971; 4.31 g, 17.1 mmol) in dichloromethane (35 ml) is added a 1M solution of boron tribromide in dichloromethane (18.2 ml). The mixture is kept under argon and stirred for 4 hours at room temperature. The mixture is poured into a saturated aqueous sodium bicarbonate solution and the aqueous layer is extracted with ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to give 2-fluoro-6-iodophenol (4.2 g).
The title epoxide (4.44 g, 86%) is prepared from the above phenol and (2S)-glycidyl 3-nitrobenzenesulfonate substantiallly as described for Epoxide 1 except using butanone as solvent.
Epoxides 56, 57, 58, 59 and 60 are prepared from 2-methoxy-5-fluorophenylboronic acid and 3-bromothiophene; 2-methoxy-6-fluorophenylboronic acid and 5-chloro-2-bromothiophene; 2-methoxyphenylboronic acid and 2-bromo-5-fluorothiophene; (3-methoxypyrid-2-yl)boronic acid and 2-bromothiophene; and 2-methoxy-6-fluorophenyl and 3-bromothiophene, respectively, by a procedure substantially similar to that described for Epoxide 30.
A slurry of 2-cyano phenol (25 g, 209.87 mmol), triethylamine hydrochloride (43.3 g, 314.81 mmol), and sodium azide (20.5 g, 314.81 mmol) in toluene (200 mL) is heated to the reflux temperature of the mixture and then the mixture is allowed to stir at reflux for 15 hours. The mixture is cooled and washed with water (200 mL). The aqueous layer is washed with ether (100 mL), made acidic with concentrated HCl, and the resulting solid is collected by filtration. The solid is washed twice with water (200 mL) and dried under vacuum at 100xc2x0 C. for 15 hours to give 33.05 g of 2-(tetrazol-3-yl)phenol (97%).
2-(Tetrazol-3-yl)phenol (32.8 g, 202.3 mmol) is dissolved in dimethylformamide (100 mL) and water (25 mL) and cooled in ice. Sodium hydroxide (8.49 g, 212.3 mmol) in water (20 mL) is added and the solution is warmed to ambient temperature. After thirty minutes, iodomethane (31.58 g, 222.5 mmol) is added neat. The solution is stirred for 15 hours then diluted with ethyl acetate (300 mL) and water (500 mL). The aqueous layer is washed three times with ethyl acetate (300 mL) and the organic layers are combined, washed three times with water (1 L), once with brine (1.2 L), dried over magnesium sulfate, filtered and concentrated in vacuo. The solid is purified by flash column chromatography (80% hexane:20% ethyl acetate gradient to 50% hexane:50% ethyl acetate as an eluent) to give 23.5 g of 2-(1-methyltetrazol-3-yl)phenol (66%).
2-(1-Methyltetrazol-3-yl)phenol (0.25 g, 1.54 mmol), (2S)-glycidyl 3-nitrobenzenesulfonate (0.42 g, 1.62 mmol), and potassium carbonate (0.45 g, 3.23 mmol) is dissolved in methyl ethyl ketone (2 mL), the mixture is heated to the reflux temperature of the mixture, and then is allowed to stir at reflux for 15 hours. The slurry is cooled, filtered and concentrated in vacuo. The solid is purified by flash column chromatography (80% hexane:20% ethyl acetate gradient to 50% hexane:50% ethyl acetate as an eluent) to give 270 mg (75%) of the title epoxide. FDMS m/e=233 (M++1).
The title epoxide is prepared from 2-hydroxy-benzaldehyde and glyoxal by the method described in Eur. J. Med. Chem., 33:181-187, 1998. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1, however, the title epoxide is used without purification as described therein.
2-Thienyl-1-methoxybenzene (10 g, 53 mmol) is cooled to xe2x88x9278xc2x0 C. in dry tetrahydrofuran (265 ml) under nitrogen while stirring. n-Butyl lithium in hexanes (1.6M, 37 ml, 59 mmol, 1.1 eq.) is added slowly and the resulting mixture is stirred cold for an hour. Chloromethyl formate (4.1 ml, 53 mmol, 1.0 equivalent) is added and the reaction is stirred cold for another hour. The mixture is allowed to warm to room temperature before quenching with saturated bicarbonate solution and ethyl acetate. The layers are separated and the organic phase is washed with brine, dried over sodium sulfate and concentrated. The residue is purified via flash chromatography in 5% ethyl acetate/hexanes to afford 7.9 g of 2-(5-methoxycarbonylthien-2-yl)-1-methoxybenzene (61%).
2-(5-Methoxycarbonylthien-2-yl)-1-methoxybenzene is demethylated with boron tribromide to give 1-(5-methoxycarbonylthien-2-yl)phenol. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxide.
A solution of 5-bromothiophene-2-carbonitrile (1.25 g, 6.65 mmol) in 50 ml of dioxane is degassed with argon, tetrakis-(triphenylphosphine)-palladium(0) (768 mg, 0.665 mmol) is added and the mixture is stirred for 5 minutes. 2-Methoxybenzene boronic acid (2.02 g, 13.3 mmol) and aqueous 2 N sodium carbonate (13.3 ml) are successively added and the mixture is stirred for 16 hours at 85xc2x0 C. Extractive work-up (2xc3x9750 ml dichloromethane and 2xc3x9730 ml water). The organic phase is dried over sodium sulfate, filtrated and evaporated. The residue (4.05 g) is purified via flash column on silica (eluent: 100% hexane greater than hexane/ethyl acetate 96:4 gradient to give 1.37 g of 2-(5-cyanothien-2-yl)anisole (96%). M+=215.
An intimate mixture of 2-(5-cyanothien-2-yl)anisole (1.2 g, 5.9 mmol) and pyridinium hydrochloride (13.7 g, 119 mmol) is heated for 1 hour to 210xc2x0 C. under argon. The mixture was cooled to ambient temperature and a 1:1 mixture of water and ethyl acetate is added to break and dissolve the solid cake formed during the reaction. The slurry is then transferred to a separation funnel and dichloromethane is added until the organic phase had a higher density than the water phase (organic phase=lower phase). The organic phase contains the desired product and is separated. The remaining aqueous phase is additionally extracted twice with dichloromethane and the collected organic phases are dried over sodium sulfate and evaporated. The residue is purified via flash column on silica (eluent: 100% hexane greater than hexane/ethyl acetate 8:2 gradient) to give 973 mg of 2-(5-cyanothien-2-yl)phenol (87%). M+=201.
To a solution of 2-(5-cyanothien-2-yl)phenol (970 mg, 4.819 mmol) in 20 ml of dry 2-butanone is added (2S)-glycidyl 3-nitrobenzenesulfonate (1.25 g, 4.82 mmol) and potassium carbonate (732 mg, 5.30 mmol) successively. After stirring for 48 hours at 75xc2x0 C., the mixture is diluted with ethyl acetate and extracted with 2N aqueous sodium hydroxide (2xc3x9730 ml) and water (1xc3x9730 ml). (M+=257).
Epoxides 66-70 are prepared by a procedure substantially similar to that described for Epoxide 65. The starting halogeno thiophenes used to prepare Epoxides 65-70 are known from the literature, see e.g., J. Mater. Chem., 5(4), 653-61, 1995; J. Chem. Soc., Perkin Trans. 2, 5:625-30, 1982; Chem. Scr., 5(5), 217-26, 1974; Bull. Soc. Chim. Fr., 11:4115-20, 1967; Bull. Soc. Chim. Fr., 11:4121-6, 1967; Bull. Inst. Chem. Res., 52(3):561-5, 1974; J. Med. Chem., 43(16):3168-3185, 2000; Bioorg. Med. Chem. Lett., 10(5):415-418, 2000; and JP 08311060.
A 25 ml 1-propanol solution of 2-methoxyphenyl boronic acid (1.2 g, 7.5 mmol) and 5-bromothien-2-ylsulfonamide (1.2 g, 5 mmol) is stirred under N2 at room temperature. Palladium(II) acetate (56 mg, 0.25 mmol), triphenylphosphine (200 mg, 0.75 mmol), 2M aqueous Na2CO3 (3 ml, 6 mmol), and 7 ml H2O are added and the resulting mixture is refluxed (xcx9c88xc2x0 C.) for 1 hour. The reaction is cooled, diluted with ethyl acetate, washed with brine, and the brine back extracted with ethyl acetate. The extracts are combined, washed with aqueous NaHCO3, brine, dried (Na2SO4), filtered, and the filtrate is concentrated. The residue is purified by chromatography (SiO2, ethyl acetate/hexane gradient) to give 943 mg (70%) of 5-(2-methoxyphenyl)thiophene-2-sulfonamide.
A 70 ml CH2Cl2 suspension of 5-(2-methoxyphenyl)thiophene-2-sulfonamide (1.0 g, 3.7 mmol) is stirred under N2 at xe2x88x9275xc2x0 C. as boron tribromide (1.1 ml, 12 mmol) is syringed into the reaction mixture. The amber solution is stirred for 30 minutes at xe2x88x9275xc2x0 C., then at 0xc2x0 C. for 2-3 hours. The reaction is quenched with ice, extracted with CH2Cl2. The extracts are washed with brine, dried (Na2SO4), filtered, and the filtrate is concentrated. The residue is purified by chromatography (SiO2, ethyl acetate/hexane gradient) to give 720 mg of 5-(2-hydroxyphenyl)thiophene-2-sulfonamide (76%).
5-(2-Hydroxyphenyl)thiophene-2-sulfonic acid amide (1.8 g, 7.1 mmol), K2CO3 (1.1 g, 8.5 mmol), and (2S)-glycidyl 3-nitrobenzenesulfonate (2.1 g, 7.8 mmol) are reacted as described for the preparation of Epoxide 1 to give 1.5 g of the title epoxide (70%).
(2-Methoxyphenyl)acetaldehyde is prepared by oxidation of 2-(2-methoxyphenyl)ethanol according to the procedure disclosed in J. Org. Chem., 49:1720, 1999. A mixture of (2-methoxyphenyl)acetaldehyde (3.8 g, 25.3 mmol) and dimethylformamide dimethyl acetal (4.52 g, 37.9 mmol) is stirred at room temperature for 1 hour. Excess of the acetal is removed under reduced pressure to leave 4.68 g of 3-dimethylamino-2-(2-methoxyphenyl)propenal (90%).
A solution of 3-dimethylamino-2-(2-methoxyphenyl)propenal (4.68 g, 22.8 mmol) and hydrazine hydrate (6.7 ml) in ethanol (100 ml) is heated at reflux for 30 minutes. The solvent is removed in vacuo and the residue is chromatographed (silica gel, dichloromethane/ethanol 95:5) to give 2.69 g of 4-(2-methoxyphenyl)pyrazole (68%).
To a solution of 4-(2-methoxyphenyl)pyrazole (300 mg, 1.72 mmol) in dichloromethane (13 ml) is added a 1M solution of boron tribromide (3.8 ml) in dichloromethane. The mixture is stirred at room temperature over night then concentrated under reduced pressure. The residue is chromatographed (silica gel, dichloromethane/ethanol 9:1) to give 270 mg of 2-(pyrazol-4-yl)phenol (98%).
2-(Pyrazol-4-yl)phenol and (2S)-glycidyl 3-nitrobenzenesulfonate are reacted as described for the preparation of Epoxide 1 to give 180 mg of the title epoxide (50%).
2-(Thien-2-yl)phenol (J. Heterocycl. Chem., 22(6):1667-9, 1985); 2-(thiazol-2-yl)phenol (Arnold, et al., WO 94/22846); 2-(5-isoxazolyl)phenol; 2-(pyrrolidin-2-on-1-yl)phenol (Tetrahedron, 26(17):4207-4212, 1970); 2-morpholinophenol; 2-piperidinophenol; 1-(2-hydroxyphenyl)piperazine; 2-(2-hydroxyphenyl)benzoxazole; 2-(2-hydroxyphenyl)benzothiazole; 2-(4,4-dimethyl-2-oxazolin-2-yl)phenol (Bioorg. Med. Chem. Lett., 6(18):2173-76, 1996); 2-(1-pyrrolidino)phenol; 2-(pyrrol-1-yl)phenol (J. Het. Chem., 8:283-287, 1971); 2-(1,3,4-oxadiazol-2-yl)phenol (WO 94/22846); 2-(isoxazol-3-yl)phenol (J. Het. Chem., 8:283-287, 1971); 2-(isothiazol-5-yl)phenol (J. Chem. Res. (S), 349, 1988; J. Chem. Res. (S), 163, 1992); 2-(1,3,4-thiadiazol-2-yl)phenol (WO 94/22846); 2-(1,2,3-thiadiazol-4-yl)phenol; 2-(oxazol-2-yl)phenol (WO 94/22846); 4-(2-hydroxyphenyl)-2(5H)-furanone (Ger. Offen. DE2829414); 4-(4-fluoro-2-hydroxyphenyl)-2(5H)-furanone (Ger. Offen. DE2829414); 2-(furan-3-yl)phenol (Ger. Offen. DE2914166); 2-thiazol-4-yl-phenol (WO 94/22846); 2-(thiazol-4-yl)phenol (WO 94/22846); 2-(4,5-dimethylimidazol-2-yl)phenol (Eur. J. Med. Chem., 33:181-187, 1998, using 4,5-dimethylimidazole instead of imidazole); 2-(3-formylpyrrol-1-yl)phenol (J. Het. Chem., 283-287, 1971 using 2,5-dimethoxy-3-formyl-tetrahydrofuran instead of 2,5-dimethoxy-tetrahydrofuran); 2-(3-methylisoxazol-5-yl)phenol (J. Org. Chem., 49:4419, 1984); and 2-(4-methylisoxazol-5-yl)phenol (Pol. J. Chem., 56:501, 1982) are reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxides.
Amines of Formula III
Amines 1-49 are prepared for use as described in Schemes 1 and 2. These amines are pictured in Tables 3-5 below.
Amines 1 and 10 may be prepared according to procedures detailed in U.S. Ser. No. 09/068,192, the teachings of which are herein incorporated by reference. Amines 11, 26 and 33 may be prepared by a procedure substantially similar to that described for Amine 1. Amines 2, 3, 8, and 9 may be prepared according to procedures detailed in U.S. Pat. No. 5,977,154, the teachings of which are herein incorporated by reference. Amines 27, 29 and 40 may be prepared by a procedure substantially similar to that described for Amine 9.
4-(2-Amino-2-methylpropyl)phenol (50.8 g, 225 mmol), 2-chloro-3-cyanopyridine (30.8 g, 222 mmol), potassium carbonate (77.7 g, 562 mmol, powdered), N,N-dimethylacetamide (609 ml), and isooctane (122 ml) are combined and heated to reflux. The water formed during the reaction is removed azeotropically via a Dean-Stark trap. After about 1-2 hours the reaction is complete. The slurry is cooled to 30xc2x0 C. and filtered. The filter cake is washed with N,N-dimethylacetamide (250 ml) and the combined organic fractions are concentrated by rotary evaporation at 80xc2x0 C. The resulting dark green oil is dissolved in dichloromethane (580 ml), and washed with water (160 ml). The phases are separated and the organic phase washed with water (250 ml). Water (1 L) is added to the organic phase and the pH adjusted to 1 with 12N aqueous hydrochloric acid (about 25 ml). The phases are separated and the acidic aqueous layer is washed with dichloromethane (250 ml). Dichloromethane (1 L) is added to the acidic aqueous phase and the pH is adjusted to 12-13 with 5N aqueous sodium hydroxide. The phases are separated and the organic phase is dried over sodium sulfate. After filtration the solution is concentrated to give 53 g of the title amine (88%).
4-(2-Amino-2-methylpropyl)phenol (55.18 g, 244.9 mmol) is added to 5.05N KOH (97.2 mmol). The mixture is warmed to 50xc2x0 C. to give a homogeneous yellow solution. Chlorobenzene (1104 ml) and N,N-dimethylacetamide (10.7 g, 122 mmol) is added and the mixture is heated to reflux (about 100xc2x0 C.). The water is removed azeotropically via a Dean-Stark trap. At about 125xc2x0 C. a solid began to form. When the pot temperature reached 132xc2x0 C. the water has been removed and the reaction mixture is a thick but stirable slurry (mechanical stirring required). The Dean-Stark trap is removed and an additional 100 ml of chlorobenzene is removed and discarded. Dry chlorobenzene (50 ml) is added to the slurry, followed by ethyl 2-chloronicotinate (50.0 g, 269 mmol) in chlorobenzene (50 ml). The slurry is heated at reflux until the reaction is complete (about 24 hours). After cooling to room temperature, water (385 ml) and 1N NaOH (25 ml, 0.1 equiv) is added to the mixture and the phases are separated. The organic phase is washed with water (285 ml) and the solution is concentrated to a net weight of 700 g (89%).
4-(2-Amino-2-methylpropyl)phenol (3.00 g, 18.2 mmol), methyl 6-chloronicotinate (3.27 g, 19.1 mmol), powdered potasssium carbonate (3.76 g, 27.2 mmol, 300 mesh), N,N-dimethylacetamide (60 ml), and toluene (15 ml) are combined and heated to reflux. The water formed during the reaction is removed azeotropically via a Dean-Stark trap. After about 2 hours, the internal temperature reached 154xc2x0 C. and the reaction is complete. The slurry is cooled to 30xc2x0 C. and filtered. The filter cake is washed with N,N-dimethylacetamide and the combined organic fractions concentrated by rotary evaporation at 75xc2x0 C. The resulting oil is dissolved in ethyl acetate (50 ml), and washed with water (30 ml). The phases are separated and the aqueous phase is extracted with ethyl acetate (20 ml) after some saturated aqueous sodium chloride solution (10 ml) is added to facilitate phase separation. The combined organic fractions are washed with water (2xc3x9730 ml) and saturated aqueous sodium chloride (30 ml) and then dried over sodium sulfate. After filtration the solution is concentrated to give 4.60 g (80%) of the title amine.
2-Cyano-3-chloropyridine (Bremner, et al., Syn. Comm., 27:1535, 1997; Kaneda, et al., Chem. Pharm. Bull., 33:565, 1985) is coupled to 4-(2-amino-2-methylpropyl)phenol to prepare the title amine by a procedure substantially similar to that described above for Amine 4.
Potassium tert-butoxide (58.6 ml, 58.6 mmol, 1M in tetrahydrofuran) is added to a solution of 3,4-dichlorothiophenol (10.0 g, 55.8 mmol) in tetrahydrofuran (300 ml) at 0xc2x0 C. and the solution stirred for 30 minutes. Methyl iodide (8.32 g, 58.6 mmol) is added dropwise and the resulting slurry is stirred for 16 hours. The solvents are removed in vacuo and the residue is dissolved in 150 ml each of methyl-t-butyl ether and 1M NaHSO4. The phases are separated and the organic layer is washed with 150 ml each of water and saturated aqueous sodium chloride. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give 9.67 g of 3,4-dichlorophenyl methylsulfide (90%).
The sulfide from above is converted to the corresponding sulfone as described below for Amine 38. The 3,4 dichloromethyl sulfone is coupled to 4-(2-amino-2-methylpropyl)phenol to prepare the title amine by a procedure substantially similar to that described above for Amine 4.
To a 1 gallon autoclave is added 2,5-dichloropyridine (123 g, 830 mmol), palladium II acetate (5.6 g, 24.9 mmol), 1,3-bis(diphenylphosphine)propane (20.5 g, 49.8 mmol), 1,1,1,3,3,3,-hexamethyldisilazane (700 ml), acetonitrile (1180 ml) and dimethylformamide (295 ml). The autoclave is pressurized to 70 psi with carbon monoxide and heated to 80xc2x0 C. for 16 hours. The reaction mixture is filtered and washed with acetonitrile. The mixture is concentrated in vacuo to 590 g and 1 L of water is added. The resulting slurry is cooled to 0xc2x0 C. and filtered to give 102.6 g (79%) of 2-carboxamido-5-chloropyridine which is used without further purification.
2-Carboxamido-5-chloropyridine is coupled to 4-(2-amino-2-methylpropyl)phenol to prepare the title Amine by a procedure substantially similar to that described above for Amine 4.
Oxalyl chloride (18.1 ml, 207 mmol) is added slowly to dimethylformamide cooled to xe2x88x9225xc2x0 C. The resulting mixture is cooled to xe2x88x9245xc2x0 C. and 2-carboxamido-5-chloropyridine (25 g, 160 mmol) is added portionwise. The reaction stirred for 30 minutes and pyridine (14.2 ml, 176 mmol) is added. The reaction stirred for 5 hours, 20 minutes and is poured into 1.5 L of water and 1 L of ethyl acetate is added. The phases are separated and the aqueous layer is extracted with 100 ml of ethyl acetate. The combined organics are washed with water (850 ml and 350 ml), saturated aqueous sodium chloride (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo to give 19.95 g (92%) of 2-cyano-5-chloropyridine which is used without further purification.
2-Cyano-5-chloropyridine is coupled to 4-(2-amino-2-methylpropyl)phenol to prepare the title amine by a procedure substantially similar to that described above for Amine 4.
To a solution of n-butyl lithium (0.544 mol) in tetrahydrofuran (700 ml) at xe2x88x9278xc2x0 C. is added a solution of 3,4-difluorobromobenzene (100 g, 0.518 mol) in 200 ml of tetrahydrofuran. After 10 minutes, a solution of dimethyl disulfide in 100 ml of tetrahydrofuran is added and the resulting reaction mixture is warmed to ambient temperature over 60 minutes. The reaction is concentrated in vacuo and the resulting oil is partitioned between 750 ml methyl-t-butyl ether and 300 ml water. The phases are separated and the organic layer is washed with 300 ml of saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil is purified by vacuum distillation to provide 43.08 g of 3,4-difluorophenyl methylsulfide.
Metachloroperbenzoic acid (60.4 mmol) is added portionwise to a solution of the sulfide (43 g, 26.8 mmol) in 1 L of dichloromethane at 0xc2x0 C. After 15 minutes, the reaction mixture is warmed to ambient temperature and stirred for 1.25 hours. The solids are removed by filtration and the resulting solution washed with 750 ml of 1M sodium bisulfite, 2 L sodium bicarbonate, 1 L water, and 750 ml saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo to give 45.17 g (88%) of the title amine.
The acetic acid salt of 4-(2-amino-2-methylpropyl)phenol (15 g, 66.5 mmol) is dissolved in 90 ml of hot water. 5N aqueous sodium hydroxide (13.98 ml, 0.0699 mol) is added and the resulting mixture is allowed to stir for one hour upon which a precipitate formed. The reaction is then placed in the refrigerator to allow more precipitation. The precipitate is filtered to afford 6.91 g of 4-(2-amino-2-methylpropyl)phenol free base.
4-(2-Amino-2-methylpropyl)phenol free base (6.91 g, 41.8 mmol) is dissolved in 100 ml of anhydrous tetrahydrofuran and the solution is purged with nitrogen. Di-t-butyl-dicarbonate (10.56 ml, 46 mmol) is added and the resulting solution is allowed to stir overnight. The reaction is concentrated, the residue dissolved in ethyl acetate, and then washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated to a clear oil. The oil is taken up in anhydrous tetrahydrofuran and diisopropylethylamine (7.94 ml, 46 mmol) is added followed by trifluoromethanesulfonic anhydride (7.67 ml, 45 mmol). The reaction is allowed to stir for 3 hours, quenched with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated to a clear solid.
A portion of the above solid (2.7 g, 6.8 mmol) is mixed with 3-cyanophenyl boronic acid (1.0 g, 6.8 mmol), aqueous potassium carbonate (2M, 7.1 ml, 14.3 mmol), lithium chloride (288 mg, 6.8 mmol) and 60 ml of tetrahydrofuran. The reaction is fitted with a condensor and purged with nitrogen before palladium(0) tetrakistriphenylphoshine is added (37.9 mg, 0.34 mmol). The reaction flask is covered with aluminum foil and the solution is brought to reflux. After 16 hours, the reaction is poured into a separatory funnel. Ethyl acetate (100 ml) is added and the organic layer is washed with water, 1N aqueous HCl, water, 1N aqueous sodium hydroxide and again with water. The organic layer is dried over sodium sulfate and concentrated to a brown solid. The crude product is purified on a silica flash column eluting with 20% ethyl acetate/80% hexanes to give 900 mg of the amine protected title amine.
The protected amine from above (1.025 g, 2.9 mmol) is placed in a flask and stirred with trifluoroacetic acid (neat). After 10 minutes, the solution is concentrated and taken up in 10 ml of methanol. This solution is then placed on a 10 g SCX column and washed with methanol (2xc3x9710 ml). The product is eluted with methanolic ammonia (2M) to give 735 mg of the title amine.
Carbonyldiimidazole (43.0 g, 265 mmol) is added in one portion to a solution of 2-chloro-5-carboxythiophene (39.2 g, 241 mmol) in 400 ml of tetrahydrofuran. The resulting mixture is allowed to stir for 60 minutes before aqueous ammonium hydroxide (28%, 125 ml) is added in one portion. After stirring for 90 minutes, the mixture is concentrated in vacuo and the residue is dissolved in ethyl acetate (750 ml). This organic solution is washed with aqueous sodium hydroxide (1N, 100 ml) and then four times with aqueous hydrochloric acid (1N, 100 ml). The organic layer is dried over sodium sulfate, filtered, and concentrated in vacuo, and dried overnight at 40xc2x0 C. in vacuo to give 22.6 g of 2-chloro-5-carboxamidothiophene.
Oxalyl chloride (8.9 ml, 102 mmol) is added dropwise to a cold solution (xe2x88x9240xc2x0 C.) of 2-chloro-5-carboxamidothiophene (15 g, 92.8 mmol) in dimethylformamide (150 ml). After the addition is complete, the reaction is allowed to stir for 2 hours before it is diluted with ethyl acetate (500 ml). The resulting mixture is washed four times with water (25 ml), dried over sodium sulfate, and concentrated in vacuo to give 12.3 g of 2-chloro-5-cyanothiophene.
2-Chloro-5-cyanothiophene (3.8 g, 26.6 mmol) and 4-(2-amino-2-methylpropyl)phenol (4.0 g, 17.8 mmol) are dissolved in dimethylsulfoxide (15 ml). Sodium hydride (60% dispersion in oil, 1.5 g) is added in portions over 2 hours. The first addition (about half of the total) is done at room temperature. The reaction is heated to 50xc2x0 C. and the remaining sodium hydride is added in portions. After the additions are complete, the reaction mixture is heated to 90xc2x0 C. and is allowed to stir for 44 hours. After allowing the reaction mixture to cool, it is diluted with dichloromethane (45 ml) and water (90 ml). The layers are separated and the organic layer is washed with water (15 ml). Water (77 ml) is added to the organic layer and the pH of the aqueous phase is adjusted to 1 with concentrated hydrochloric acid (1.9 ml). The aqueous layer is washed with dichloromethane (14 ml) and then the pH is adjusted to 13 with aqueous sodium hydroxide (5N, 14 ml). The aqueous layer is extracted three times with dichloromethane (90 ml, 2xc3x9745 ml). The extracts are combined, dried over sodium sulfate, and concentrated in vacuo to give 3.5 g of the title amine.
2-Methyl-hydroxy-phenol (15.0 g, 0.12 mol), 2-nitro propane (60.8 ml, 676 mmol), potassium t-butoxide (6.77 g, 60 mmol) and diglyme (150 ml) are mixed together in a reaction vessel and said vessel is fitted with a Dean-Stark water trap. The reaction is heated to 134xc2x0 C. until water and solvent began to collect in the trap. The reaction is slowly heated to 149xc2x0 C. and then is allowed to cool back down to 130xc2x0 C. at which point the reaction is stirred for 3 hours. Reaction is cooled to room temperature and water (20 ml) is added. After concentrating to about half the volume, water (100 ml) is added and the mixture is extracted with ethyl acetate (2xc3x97100 ml). The organic layer is then washed with 1N aqueous hydrochloric acid and water, dried over sodium sulfate and concentrated to a brown oil. A mixture of ethyl acetate and hexanes, (300 ml, 1:4 ethyl acetate/hexanes) is added and product is triturated.
The product from above (7.0 g) is taken up in methanol and acetic acid and 5% palladium on carbon is added. Hydrogen gas is injected into the reaction vessel up to 50 p.s.i. The mixture is then heated to 50xc2x0 C. and shaken for 16 hours. The catalyst is filtered and the reaction is concentrated. Ethyl acetate (400 ml) is added and product is filtered to give 7.55 g of 2-(2-amino-2-methylpropyl)phenol acetic acid salt. 2-(2-Amino-2-methylpropyl)phenol acetic acid salt is converted to its free base form, the free base is reacted with di-t-butyl-dicarbonate, and the protected amine is reacted with 4-cyanophenyl boronic acid to prepare the title amine substantially as described above for Amine 41.
Amines 5, 13-23, 25, 28, 30, 32, 34, 35, 37 and 39 are prepared by procedures substantially similar to that described for Amine 4. Amines 42 and 47 are prepared by procedures substantially similar to that described for Amine 41. Amines 44-46 are prepared by procedures substantially similar to that described for Amine 43. Amine 49 is prepares by procedures substantially similar to that described for Amine 48.
Aryl Halides of Formula V
Aryl halides 1-14 are prepared for use as described in Scheme 2. These aryl halides are pictured below in Tables 6 and 7.
Representative Procedure 1: Preparation of Aryl Halides
(2S)-1-(2-iodophenyloxy)-2,3-epoxypropane (Epoxide 22, 8 mmol) or (2S)-1-(2-iodo-6-fluorophenyloxy)-2,3-epoxypropane (Epoxide 55) is reacted with an equimolar amount of an amine of formula III (Amines 2-5, 9, 10, 12, 31, 36 or 40) in 100 ml of refluxing dry ethanol overnight. After evaporation of the solvent the residue is purified via flash chromatography on silica gel using a dichloromethane-dichloromethane/ethanolic ammonia gradient (100 to 95:5).
Boronic Acids
The following boronic acids or cyclic esters are obtained from commercial sources for use as described in Scheme 2.